B-cell tolerance is affected by central and peripheral censoring mechanisms at several checkpoints. Dysregulation at these checkpoints can potentially lead to humoral autoimmunity. To what extent these checkpoints are infringed in spontaneous, systemic autoimmune disease remains unknown. A major challenge of contemporary autoimmunity research is to fathom the precise mechanisms that tip the balance from tolerance towards autoimmunity, in spontaneous disease. The availability of B6 mice bearing different lupus susceptibility loci, as congenic intervals, now allows us to ask how these loci might compromise B cell tolerance. In particular, in this proposal, we will utilize B6 congenics bearing five different NZM2410-derived lupus susceptibility loci. The goals of this proposal are: (1) To ascertain the impact of lupus susceptibility loci (Sle1a, Sle1b, Sle2, Sle3 and Sle5) on B-cell tolerance to DNA, using anti-DNA immunoglobulin transgenic mice. (2) To ascertain the impact of lupus susceptibility loci (Sle1a, Sle1b, Sle2, Sle3 and Sle5) on B-cell tolerance to non-nuclear antigens, using the anti-HEL immunoglobulin transgenic model. (3) To elucidate the molecular pathways that may be infringed by the lupus susceptibility loci, as self tolerance is actively breached, using naive B-cells purified from immunoglobulin transgenic models. Collectively, the above studies will indicate how loci/genes that predispose to systemic autoimmunity might tip the balance away from self-tolerance. Understanding how these loci/genes function will not only broaden our perspective of this disease, but will also point to potential targets for therapeutic intervention.